Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism. INTRODUCTION: A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline. METHODS: The ~ 3-week protocol included two segments: "baseline," ≥ 10-h sleep opportunity/day × 5 days; "forced desynchrony" (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20-59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (ß) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure. RESULTS: Plasma P1NP levels declined significantly within the first 10 days of FD ([Formula: see text] = - 1.33 µg/L per 24 h, p < 0.0001) and remained lower than baseline with prolonged exposure out to 3 weeks ([Formula: see text] = - 0.18 µg/L per 24 h, p = 0.67). As previously reported, levels of a bone resorption marker (C-telopeptide (CTX)) were unchanged. CONCLUSION: Sleep restriction with concurrent circadian disruption induced a relatively rapid decline in P1NP (despite no change in CTX) and levels remained lower with ongoing exposure. These data suggest (1) even brief sleep restriction and circadian disruption can adversely affect bone metabolism, and (2) there is no P1NP recovery with ongoing exposure that, taken together, could lead to lower bone density over time.

Decreased sensitivity of the circadian system to light in current, but not remitted depression.

BACKGROUND: Misalignment of circadian timing in patients with depression has commonly been reported, but the underlying mechanisms are not known. Individual differences in the sensitivity of the circadian system to light affect how the biological clock synchronizes with the external environment and can lead to misalignment of rhythms. We investigated the sensitivity of the circadian system to light in unmedicated (for >3 months) women with a current or previous diagnosis of major depression, and healthy controls. METHODS: Baseline melatonin levels in dim light (<1 lux) were assessed, followed by melatonin levels in normal indoor lighting of 100 lux in order to determine melatonin suppression. RESULTS: Patients currently experiencing a depressive episode showed significantly lower levels of melatonin suppression to light compared to remitted patients and controls, with large effect sizes. Remitted patients and controls showed similar suppression. LIMITATIONS: The relatively small sample, and lack of long-term, within subject assessments, make it difficult to determine the potential causal role of reduced light sensitivity in the development of circadian disruption. CONCLUSIONS: We conclude that hyposensitivity of the circadian system to light may contribute to circadian misalignment in patients with depression. Interventions that increase sensitivity to light or provide stronger light cues may assist in normalizing circadian clock function.

The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose.

RATIONALE: Disturbances of the circadian system are common in depression. Though they typically subside when depression is treated with antidepressants, the mechanism by which this occurs is unknown. Despite being the most commonly prescribed class of antidepressants, the effect of selective serotonin reuptake inhibitors (SSRIs) on the human circadian clock is not well understood. OBJECTIVE: To examine the effect of the SSRI citalopram (30 mg) on the sensitivity of the human circadian system to light. METHODS: This study used a double-blind, placebo-controlled, within-subjects, crossover design. Participants completed two melatonin suppression assessments in room level light (~ 100 lx), taking either a single dose of citalopram 30 mg or a placebo at the beginning of each light exposure. Melatonin suppression was calculated by comparing placebo and citalopram light exposure conditions to a dim light baseline. RESULTS: A 47% increase in melatonin suppression was observed after administration of an acute dose of citalopram, with all participants showing more suppression after citalopram administration (large effect, d = 1.54). Further, melatonin onset occurred later under normal room light with citalopram compared to placebo. CONCLUSIONS: Increased sensitivity of the circadian system to light could assist in explaining some of the inter-individual variability in antidepressant treatment responses, as it is likely to assist in recovery in some patients, while causing further disruption for others.

Evening types demonstrate reduced SSRI treatment efficacy.

Selective serotonin reuptake inhibitors (SSRIs) have a profound effect on the circadian system's response to environmental light, which may impact treatment outcomes for patients depending on their habitual light exposure patterns. Here, we investigated the relationship between time-of-day preference, depressive symptoms and self-reported antidepressant treatment response. Evening types reported having taken a higher number of antidepressant medications in the previous 5 years and lower SSRI efficacy than morning types. While undergoing SSRI treatment, evening types also reported more depressive symptoms and suicidality. It is concluded that time-of-day preference may prove informative in predicting SSRI treatment responses.

24-hour profile of serum sclerostin and its association with bone biomarkers in men.

The osteocyte's role in orchestrating diurnal variations in bone turnover markers (BTMs) is unclear. We identified no rhythm in serum sclerostin (osteocyte protein). These results suggest that serum sclerostin can be measured at any time of day and the osteocyte does not direct the rhythmicity of other BTMs in men. INTRODUCTION: The osteocyte exerts important effects on bone remodeling, but its rhythmicity and effect on the rhythms of other bone cells are not fully characterized. The purpose of this study was to determine if serum sclerostin displays rhythmicity over a 24-h interval, similar to that of other bone biomarkers. METHODS: Serum sclerostin, FGF-23, CTX, and P1NP were measured every 2 h over a 24-h interval in ten healthy men aged 20-65 years. Maximum likelihood estimates of the parameters in a repeated measures model were used to determine if these biomarkers displayed a diurnal, sinusoidal rhythm. RESULTS: No discernible 24-h rhythm was identified for sclerostin (p = 0.99) or P1NP (p = 0.65). CTX rhythmicity was confirmed (p < 0.001), peaking at 05:30 (range 01:30-07:30). FGF-23 levels were also rhythmic (p < 0.001), but time of peak was variable (range 02:30-11:30). The only significant association identified between these four bone biomarkers was for CTX and P1NP mean 24-h metabolite levels (r = 0.65, p = 0.04). CONCLUSIONS: Sclerostin levels do not appear to be rhythmic in men. This suggests that in contrast to CTX, serum sclerostin could be measured at any time of day. The 24-h profiles of FGF-23 suggest that a component of osteocyte function is rhythmic, but its timing is variable. Our results do not support the hypothesis that osteocytes direct the rhythmicity of other bone turnover markers (CTX), at least not via a sclerostin-mediated mechanism.

Constraint is associated with earlier circadian phase and morningness: Confirmation of relationships between personality and circadian phase using a constant routine protocol.

Associations among personality, diurnal preference, and circadian phase were investigated using a constant routine laboratory protocol. One hundred and sixty-eight healthy participants aged 18-30 years (Women n = 68) completed either a 30- or 50-hour constant routine under dim-light conditions (<3 lux), during which circadian phase was measured from core body temperature and melatonin. Prior to laboratory admission, self-report measures of personality and diurnal preference were also obtained. The personality trait of Constraint correlated positively with morning diurnal preference and earlier circadian phase, with circadian phase partially mediating the relationship between Constraint and diurnal preference. No other personality variables correlated with circadian phase. Sex was an important covariate in several of the relationships investigated due to lower levels of Constraint and later CBT phase amongst men and was thus controlled for in all relevant analyses. Findings from this highly controlled study are consistent with previous field research in suggesting that earlier circadian phase is associated with the personality trait of Constraint.

Investigating the relationship between sleep and macronutrient intake in women of childbearing age.

BACKGROUND/OBJECTIVE: Reduced sleep is a strong and independent risk factor for weight gain and obesity. Maternal obesity preconception and throughout gestation can increase the risk of adverse pregnancy outcomes and impact on offspring health in later life. This study investigated the relationship between sleeping behaviour and macronutrient intake in childbearing aged women. SUBJECTS/METHODS: We used cross-sectional data from the Australian Longitudinal Study on Women's Health 1973-78 cohort, aged 31-36 years in 2009 (n=8200). Subjective sleeping behaviour was reported and macronutrient intake was measured using a validated food frequency questionnaire. Latent class analysis (LCA) was used to derive sleeping patterns. Multivariate regression analysis was used to investigate the relationships between sleep and macronutrient intake. RESULTS: LCA identified three sleep patterns: (LC1) average sleep (~8 h) with no adverse sleep-related symptoms (n=3570); (LC2) average sleep (~8 h) with sleeping difficulties and severe tiredness (n=2109); and (LC3) short sleep (~6 h) with sleeping difficulties and severe tiredness (n=915). In fully adjusted models, LC2 was inversely associated with percentage energy as protein (b=-0.24; P=0.01) and the protein-to-carbohydrate ratio (b=-0.01; P<0.05). LC3 was positively associated with percentage of energy as fat (b=0.29; P=0.01), saturated fat (b=0.24; P=<0.001) and monounsaturated fat (b=0.09; P=0.04). CONCLUSIONS: Sleeping behaviour patterns were associated with macronutrient intake in childbearing aged women. Improved sleep patterns, together with diet and physical activity strategies, may make it easier for women to achieve a balanced diet and optimise their weight status in preparation for pregnancy.

Biological Rhythms Workshop IC: sleep and rhythms.

Rhythms of sleep and wakefulness (typically measured as rest/activity rhythms) are among the most prominent of biological rhythms and therefore were among the first to be recorded in early chronobiological studies. These rhythms can provide useful information about the central biological clock, although an appreciation of the problems associated with using rest/activity to infer central clock function is important in the design and interpretation of chronobiological experiments in both animals and humans. Here, we review the anatomical and neurophysiologic bases of sleep regulation in mammals as well as similarities and differences between the sleep of humans and that of other organisms. We outline how human sleep is measured, the role of the circadian system in models of human sleep regulation, and human circadian rhythm sleep disorders. Although the function of sleep is still not completely understood, sleep has a critical role for human health, and we have attempted to outline the role that the circadian timing system has in regulating human sleep and in contributing to sleep disorders.

Estrous odors and sexually conditioned neutral odors activate separate neural pathways in the male rat.

Olfactory stimuli play important roles in sexual behavior. Previous studies have demonstrated that both estrous odors and initially neutral odors paired with copulation influence the sexual behavior of male rats. The present study examines the pattern of neural activation as revealed by Fos immunoreactivity (Fos-IR) following exposure to bedding scented with either a neutral odor (almond) paired previously with copulation, estrous odors or no odor. Following exposure to estrous odors Fos-IR increased in the accessory olfactory bulb, medial amygdala, medial bed nucleus of the stria terminalis, medial preoptic area, ventromedial hypothalamus, ventral tegmental area, and both the nucleus accumbens core and shell. Conversely, following exposure to the sexually conditioned odor Fos-IR increased in the piriform cortex, basolateral amygdala, nucleus accumbens core, and the anterior portion of the lateral hypothalamic area. In addition, following exposure to almond odor Fos-IR increased in the main olfactory bulb independent of its pairing with copulation. These patterns of Fos-IR following exposure to estrous or sexually conditioned odors were not influenced by either the addition or omission of the other type of odor. These findings demonstrate that estrous and sexually conditioned odors are processed by distinct neural pathways and converge in the nucleus accumbens core, suggesting that this structure has a unique role in processing sexual stimuli of both pheromonal and olfactory natures.